Even though over 1.1 billion persons worldwide smoke tobacco, current therapies to reduce smoking (e.g., the nicotine patch) have a low success rate after one year. There is an urgent need to develop a specific medication that can be used in conjunction with counseling and self-help programs to decrease smoking and save lives. Despite clear evidence that smoking tobacco is the leading cause of preventable death, almost one in four American adults smoke tobacco.
The major pharmacologically active chemical in tobacco is (S)-nicotine, which is primarily responsible for the pharmacological and behavioral effects of smoking including the stimulant and addictive properties. Nicotine causes complex central nervous system, behavioral, cardiovascular, endocrine, neuromuscular and metabolic effects in humans. Nicotine is one of the most addictive substances known. After administration to humans, nicotine undergoes extensive metabolism which reduces its pharmacological activity. The majority of such nicotine is metabolized via a cytochrome P-450 2A6 (CYP2A6)-dependent pathway to form nicotine Δ1′,5′-iminium ion. In the presence of aldehyde oxidase, nicotine Δ1′,5′-iminium ion is converted to cotinine. While cotinine can be further metabolized, cotinine has a long half-life and is a useful marker for both nicotine exposure and is also a functional indicator of CYP2A6 activity. In humans, a similar metabolic pathway occurs in the lung and respiratory system and utilizes a related enzyme system, CYP2A13.
Tobacco users (e.g., smokers) adjust their tobacco use to maintain a certain blood and brain level of nicotine. Recently, it has been observed that individuals with a decreased ability to metabolize nicotine (so-called poor metabolizers because they possess inactive alleles that code for the prominent enzyme that metabolizes nicotine and terminates its activity) are protected from becoming dependent on nicotine and have a reduced lung cancer risk. However, most smokers are not poor metabolizers of nicotine.
Reducing nicotine intake concommittantly reduces the intake or exposure of a tobacco user or smoker to other tobacco and tobacco smoke contaminants and their metabolites. Many of the metabolites and constituents of tobacco and tobacco smoke are toxic, for instance, the highly carcinogenic tobacco-specific N-nitrosamines. Such tobacco-specific N-nitrosamines play an important role in tobacco-related human lung cancer, due to their strong ability to induce lung tumorigenesis. It has been shown that hepatic CYP2A6 is involved in the mutagenic activation N-nitrosamines such as NNK, and that inhibition of CYP2A6 with a selective inhibitor, in turn, inhibits lung tumorigenesis in female A/J mice. In the lung, it is likely that CYP2A13 activates tobacco-related nitrosamines to mutagens and causes lung or other respiratory organ cancers.
The present invention meets these and other needs by providing novel compounds, pharmaceutical compositions, and methods of treatment which can be useful in treating tobacco addiction, reducing tobacco consumption, and in inhibiting CYP2A6 and/or CYP2A13 activity generally and, particularly, with respect to the metabolism of nicotine by CYP2A6 and/or CYP2A13. In vivo studies of two compounds administered to rats addicted with nicotine showed potency at reducing nicotine self-administration.